CD1 presentation of self glycolipids and lipopeptides to T cells T cells that recognize autoantigens play a central role in psoriasis, thyroiditis, diabetes, multiple sclerosis, rheumatoid arthritis and other human autoimmune diseases. For many years all autoantigens for T cells were thought to be peptides bound to MHC proteins. However, new evidence shows that cellular lipids activated T cells when bound to CD1 proteins expressed on Langerhans cells and other dendritic cells. Recent studies show that CD1 and lipid autoreactive T cells occur frequently in individuals, such that they can now be considered a normal part of human immune responses. In particular, CD1a activates T cells that make IL-22, a cytokine that contributes to psoriasis. Whereas nearly all prior study of T cell autoantigens have focused on peptides, these findings considerably broaden the spectrum of autoantigens to include a variety of cellular lipids. Discovery of CD1 autoreactive T cells opens up a new and general pathway for discovering autoantigens that contribute to autoimmune disease and the use of lipids to treat autoimmune diseases. Whereas mouse models provide important information about in vivo function, tissue antigens and CD1-mediated T cell responses differ between mouse and human systems. Therefore, this proposal uses human tissues from normal donors and autoimmune disease patients to isolate new antigens and new T cell types. Specifically, experiments will use mass spectrometry to broadly measure the mass and chemical properties of lipids bound to human CD1a, CD1b and CD1c proteins. From this large pool of candidate autoantigens, lipids that lead to the strongest T cell activation will be identifed using T cell clones and polyclonal T cells from patients. After isolating antigenic compounds from tissues by liquid chromatography, their molecular structures will be solved by mass spectrometry. CD1 proteins and antigens will be used to measure T cell responses in normal donors and patients to test new general hypotheses about the role of CD1 and interleukin-22 in skin and thyroid autoimmunity.